Hemocompatible nucleosome-inspired heparin-mimicking hydrogel microspheres for safe and efficient extracorporeal removal of circulating histones in critically ill patients†

Abstract

Circulating histones have been identified as essential mediators that lead to hyperinflammation, platelet aggregation, coagulation cascade activation, endothelial cell injury, multiple organ dysfunction, and death in severe patients with sepsis, multiple trauma, COVID-19, acute liver failure, and pancreatitis. Clinical evidence suggests that plasma levels of circulating histones are positively associated with disease severity and survival in patients with such critical diseases. However, safe and efficient therapeutic strategies targeting circulating histones are lacking in current clinical practice. Extracorporeal blood purification, a widely used life support technique in intensive care units, is a promising therapeutic option for eliminating circulating histones. Inspired by electrostatic interactions between DNA chains and histones in natural nucleosomes, we propose a “one stone kills two birds” strategy to combat histone-related critical diseases by developing heparin-mimicking hydrogel microspheres (RCHMs). On one hand, the heparin-mimicking hydrogel structure inside RCHMs contains a large number of carboxyl and sulphonic acid groups by in situ cross-linking polymerization, which endows the RCHMs with excellent hemocompatibility. On the other hand, the RCHMs can adsorb circulating histones through electrostatic interactions. Our results demonstrate that the RCHMs do not cause significant hemolysis, blood cell activation and complement activation, with improved anti-protein contamination properties. The tailored RCHM microspheres (A₃M₁) can efficiently and selectively adsorb 91.16% of calf thymus histones with an adsorption capacity of 20.47 μg mg⁻¹ within 4 h. Moreover, the RCHMs significantly attenuate histone-mediated thrombocytopenia, platelet aggregation, and endothelial cell death. Therefore, the RCHMs are promising hemoperfusion adsorbents for extracorporeal removal of circulating histones from the blood of critically ill patients, providing a new insight into the management of multiple histone-related disorders.